Frontier: Key pathway helps keep fear memories intact

A hallmark of anxiety and post-traumatic stress disorder is the inability to separate the intense fear of a past event from the present-day situations that recall it (see “Memory Research Helps Tone Down What’s Best Forgotten,” July-August BrainWork). In scientific parlance, the uncoupling of such links is called extinction—a process that many treatments for fear-related disorders attempt to speed up.

Now, Li-Huei Tsai of the Massachusetts Institute of Technology and colleagues have found a biochemical pathway that underlies extinction, which may open the door to new medications. Previous research suggested that a protein dubbed Cdk5 plays many roles in the brain changes that support learning. In the new study, published in September in Nature Neuroscience, Tsai and colleagues tested Cdk5 in extinction (which is, in its own right, a form of learning).

The team trained mice to associate a specific cage environment with a mild shock to the foot. In the subsequent “extinction” phase, the mice were put in the cage without receiving a shock. After four to six such exposures, the mice stopped freezing in place at the sight of the environment. They had learned that it was no longer dangerous.

When the investigators gave the mice a Cdk5 blocker, however, the animals lost their fear after only two or three training sessions—suggesting that, normally, Cdk5 has some role in causing memory to persist.

“From an evolutionary point of view, a mechanism to prevent extinction seems reasonable,” Tsai says. “For example, an animal that quickly lost its fear of a place where a predator attacked would have reduced chances for survival.”

The authors predict that medications targeting Cdk5, or other mechanisms that hold off extinction, may be promising treatments for emotional disorders.

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